This invention relates to preventives and remedies for inflammatory intestinal disease which contain an anti-Fas ligand antibody as their effective component.
Fas is a cell surface antigen which transmits apoptosis signal to the cell, and Fas is recognized by Fas antibody (Yonehara, S. et al., J. Exp. Med., vol. 169, 1747-1756, 1989) which is a monoclonal antibody produced by immunizing a mouse with human fibroblast. Fas gene was recently cloned by Itoh, N. et al., and it was then found out that Fas is a cell membrane protein of about 45 kD, and from the amino acid sequence, it was revealed that Fas is a member of TNF receptor family (Cell, vol. 66, pages 233-243, 1991). Mouse Fas gene was also cloned (Watanabe-Fukunaga, et al., J. Immunol., vol. 148, pages 1274-1279, 1992), and the expression of Fas mRNA in thymus, liver, lung, heart, ovary was confirmed.
Human Fas ligand is a polypeptide which has been reported by Nagata et al. to be a biological molecule which induces apoptosis of Fas-expressing cells (Takahashi, T. et al., International Immunology, vol. 6, pages 1567-1574, 1994). Human Fas ligand is a glycosilated Type II membrane protein of TNF family with a molecular weight of about 40 kD. As in the case of TNF, human Fas ligand in the human body is estimated to be in the form of a trimer (Tanaka, M. et al., EMBO Journal, vol. 14, pages 1129-1135, 1995). The extracellular domain of the human Fas ligand is highly homologous with the extracellular domain of rat Fas ligand (Suda, T. et al., Cell, vol. 75, pages 1169-1178, 1993) and mouse Fas ligand (Takahashi, T. et al., Cell, vol. 76, pages 969-976, 1994). The human Fas ligand recognizes not only the human Fas but also the mouse Fas to induce the apoptosis, and vice versa, the rat Fas ligand and the mouse Fas ligand also recognize the human Fas to induce the apoptosis. Shirakawa, K. et al. has produced an anti-Fas ligand antibody, and disclosed an assay method for measuring Fas ligand in human body fluids using the thus produced antibody (International Patent Application Publication No. WO 97/02290).
Considerable researches have also been done on the mechanism of signal transduction in the cell upon the Fas-mediated apoptosis, and identification and cloning of the factors which interacts with the intracellular domain of the Fas, in particular, the region called xe2x80x9cdeath domainxe2x80x9d to transmit or block the signal have been reported. Possibility of the involvement of interleukin-1-converting enzyme (ICE)-related thiol proteases in the signal transduction of the Fas-mediated apoptosis has also been indicated.
Possibility of the involvement of the Fas/Fas ligand system in functions other than the apoptosis has also been indicated, for example, the possibility of the function that the Fas/Fas ligand system act with neutrophil to induce inflammation has also been indicated (Kayagaki, N. et al., Rinshou Men-eki (Clinical Immunology), vol. 28, pages 667-675, 1996).
Relationship of the apoptosis, in particular, the Fas-mediated apoptosis with various diseases and physiological phenomena has been recently indicated. For example, possibility has been indicated for involvement of abnormal Fas-mediated apoptosis in the death of hepatocytes in viral fulminant hepatitis, in some types of autoimmune diseases, and the like. Also disclosed is a therapeutic drug for hepatitis containing an anti-human Fas ligand antibody as its effective component (JP-A 1997-124509).
Inflammatory intestinal disease may be etiologically categorized into specific disease and nonspecific disease. The phanerogenic specific diseases include inflammatory intestinal disease induced by infection, drugs, chemicals and radiation, and ischemic colitis. The nonspecific disease is called idiopathic inflammatory intestinal disease, and typical such diseases are Crohn""s disease and ulcerative colitis, both of which are cryptogenic, intractable, chronic intestinal diseases which experience active and remissive stages. Although ulcerative colitis is cryptogenic, involvement of immunopathological mechanisms and psychological factors in the ulcerative colitis have been indicated. The patients of ulcerative colitis are mainly adults of under 30 although infants and adults over 50 occasionally suffer from ulcerative colitis. The ulcerative colitis is an inflammatory disease of intestine, and more specifically, an inflammatory disease of rectum, and mucous membrane and its substratum are the main lesions. This disease is generally associated with hemorrhagic diarrhea and systemic conditions of varying degree, and when the patients suffer from this disease for a prolonged period and the lesion extends to the entire intestine, the lesion is likely to undergo transformation. Crohn""s disease is a cryptogenic disease and the patients are mainly young adults. The Crohn""s disease is associated with granulomatous inflammation lesion exhibiting edema, fibrosis (myofibrosis), and ulcer, and such lesion may occur in various parts of the digestive tract. Metastatic lesion is occasionally found in places other than the digestive tract (in particular, in skin). The Crohn""s disease was previously called terminal ileitis associated with the lesion in the terminal ileum. However, it has been clearly found that this disease may occur at every parts of the digestive tract from oral cavity to anus. The clinical image of the Crohn""s disease varies depending on the place of the lesion and its coverage, and the disease is typically associated fever, malnutrition, anemia, arthritis, iritis, liver damage and other systemic complications (Takazoe, M. et al., Naika (Internal Medicine), vol. 77, No.2, pages 257-264, 1996).
With the progress in immunology and molecular biology, etiology of idiopathic inflammatory disease has been widely investigated and gradually clarified from the points of MHC class II of inflammatory cells such as lymphocyte and epithelial cell, cytokines, adhesive molecules, inflammatory substances such as arachidonic acid and leukotriene, active oxygen, etc. The detailed etiology, however, is yet unknown. In view of such uncertainty in the mechanism of its onset, it is impossible to conduct an etiological therapy for the inflammatory intestinal disease as a routine clinical practice, and the therapies presently conducted are nonspecific therapies (Matsuhashi, N. et al., Naika (Internal Medicine), vol. 77, No.2, pages 227-229, 1996). Current standard therapy for the inflammatory intestinal disease is symptomatic treatment using salazosulfapyridine, steroids, and the like (Current Therapy for Disease in Digestive Apparatus, ""95-""96, pages 175-182, 1995). Salazosulfapyridine, however, suffers from side effects such as nausea, headache, fever, rash, hemolytic anemia, epidermolysis, granulocytopenia, fibrous alveolitis, headache, pancreatitis, and male infertility (Allegayer et al., Gastrointestinal pharmacology, vol. 24, pages 643-658, 1992). Steroids also suffer from various serious side effects (Kashiwazaki, S. et al., Sogo Rinsho (General Clinical Medicine), vol. 43, 1725-1729, 1994). Thus, salazosulfapyridine and steroids need careful managements in their timing, dose, duration of administration.
Iwamoto et al. has reported expression of Fas/Fas ligand in epithelium of intestinal crypt of the patient suffering from ulcerative colitis (J. Pathology, vol. 180, pages 152-159, 1996). Ruggero De Maria et al. has reported expression of Fas ligand on T cell of tunica propia of human intestinal mucous membrane (J. Clin. Invest. vol. 97, pages 316-317, 1996). Jorn Strater et al. has reported that epithelial cell of intestinal mucous membrane from the patient suffering from ulcerative colitis exhibits resistance to apoptosis by TNF while its exhibits sensitivity to the apoptosis by anti-human Fas antibody, CH-11; that Fas ligand is expressed in interstitial lymphocytes of the intestine; and that increase in apoptosis of colonocyte and expression of the Fas ligand are found in ulcerative colitis (Gastroenterology, vol. 113, 160-167, 1997). In the meanwhile, there have been reported that the mechanism of Fas-mediated cell death is far from being dominant in cytotoxicity of intestinal epithelial cell from the patient suffering from ulcerative colitis and some other courses of cytotoxicity should be present (Abstracts of 83rd Meeting of Japan Gastroenterology Society, page 243, Entero-56, 1997), and that while expression of Fas/Fas ligand was found together with the presence of the apoptotic cell in the case of ulcerative colitis, expression of Fas/Fas ligand was not recognizable in the epithelium of crypt in the case of the other inflammatory intestinal diseases such as Crohn""s disease and enteritis induced by drug or radiation, and the like (Igaku-no Ayumi (Progress in Medicine), vol. 178, pages 651-654, 1996). In addition, there has been reported that knockout mouse of interleukin-2 exhibited symptoms similar to human inflammatory intestinal disease (Sadlack, B. et al., Cell, vol. 75, pages 253-261, 1993), and the reports using this model (Burkhad, K. et al., Eur. J. Immunol., vol. 25, pages 2572-2577, 1995; Ludviksson, B. R. et al., J. Immunol., vol. 158, pages 104-111, 1997) indicate that inhibition of the Fas-mediated apoptosis is the etiology for the inflammatory intestinal disease. As described above, the issue of the involvement of the Fas/Fas ligand-mediated apoptosis in the inflammatory intestinal disease such as ulcerative colitis and Crohn""s disease has been a divisive question among the workers in the field, and no unified view has been established as to whether the apoptosis is involved in the pathology or not, and if involved, whether the pathology is caused by the induction of the apoptosis or by the inhibition of the apoptosis. As described above, involvement of direct or indirect Fas/Fas ligand-mediated apoptosis in the onset of the pathology of the inflammatory disease is yet unknown.
The report of the anti-Fas ligand antibody (International Patent Application Publication No. WO 97/02290), supra describes that such antibody may be effective in preventing or treating the diseases such as ulcerative colitis and Crohn""s disease wherein the involvement of the Fas/Fas ligand has been indicated. As in the case of such report, it has been possible to postulate the effectivity of the anti-Fas ligand antibody in ulcerative colitis and Crohn""s disease. The postulation, however, was supported with no specific data or grounds, and there are also reports which are contradictory to such postulation. In short, effectivity of the anti-Fas ligand antibody in the inflammatory intestinal disease such as ulcerative colitis and Crohn""s disease is yet unknown. There has also been reported that an agonist for xcex3-retinoic acid receptor and artificial veto cell which have apoptosis-inducing action are effective in treating the Crohn""s disease (International Patent Application Publication No. WO 97/13505 and International Patent Application Publication No. WO 96/32140).
In view of the situation as described above, namely, the uncertainty of the involvement of the Fas/Fas ligand in the inflammatory intestinal disease such as ulcerative colitis and Crohn""s disease and the presence of the report describing the effectivity of the apoptosis-inducing substance in the inflammatory intestinal disease, it has been utterly unknown whether the anti-Fas ligand antibody having the apoptosis-suppressing action is effective in the inflammatory intestinal disease such as ulcerative colitis and Crohn""s disease, and demonstration of the effectivity has been eagerly awaited. Such demonstration could not be realized due to the absence of appropriate findings.
An object of the present invention is to provide a preventive and therapeutic agent for inflammatory intestinal disease which acts by the novel mechanism of suppressing apoptosis. More specifically, the present invention provides a preventive and therapeutic agent for inflammatory intestinal disease which contains an anti-Fas ligand antibody as its effective component and a therapeutic method wherein such agent is used.
The inventors of the present invention have conducted intensive studies on the relation between the apoptosis and the inflammatory intestinal disease in order to save those suffering from the inflammatory intestinal disease, and found that the pathology is improved in the model of inflammatory intestinal disease by the anti-Fas ligand antibody. The present invention has been completed on the bases of such finding.
Accordingly, the present invention is directed to a preventive and therapeutic agent as described below as well as a prophylactic and therapeutic method wherein such agent is used.
(1) A preventive and therapeutic agent for at least one disease selected from the group consisting of inflammatory intestinal disease induced by infection, drugs, chemicals and radiation, ischemic colitis, and idiopathic inflammatory intestinal disease containing an anti-Fas ligand antibody as its effective component.
(2) A preventive and therapeutic agent according to (1) wherein said anti-Fas ligand antibody is a humanized anti-Fas ligand antibody.
(3) A preventive and therapeutic agent according to (1) or (2) wherein said disease is idiopathic inflammatory intestinal disease.
(4) A preventive and therapeutic agent according to any one of (1) to (3) wherein said disease is at least one disease selected from Crohn""s disease and ulcerative colitis.
(5) A preventive and therapeutic agent according to any one of (1) to (4) wherein said agent produces its therapeutic effects on said disease in its active stage.
(6) A preventive and therapeutic agent according to any one of (1) to (5) wherein said agent has an action selected from the group consisting of improvement in mucous lesion, improvement in intestine adhesion, and improvement of diarrhea.
(7) A preventive and therapeutic agent containing as its effective component an anti-Fas ligand antibody which has the effect of improving the pathology of inflammatory intestinal disease induced by a chemical or a drug or its model.
(8) A preventive and therapeutic agent according to (7) wherein said model is a model of inflammatory intestinal disease induced by TNBS.